This article was originally published on MedicalDesign.com in September 2014.
Stuart Williams, PhD, came from a family entrenched in medical science and technology. His father was a chemist and he became a vascular biologist, with a PhD in biology and chemistry. He got his first incentive to go into medical grafts when his father needed a bypass graft and he saw that what the medical world was using in this area was either some type of plastic or metal. That got him interested in finding out what it would take to create hybrid devices that were both standard materials but integrated with actual living cells so they would integrate better into the human body and work longer and better.
“I did my PhD at the University of Delaware, and my postdoctoral studies in cardio-vascular pathology at the Yale School of Medicine. Then I went to Philadelphia and went to Jefferson Medical College. That’s where, with colleagues, we started putting devices together where cells were a big part of those devices. We worked on vascular grafts and we are still working on these devices,” said Williams.
Along the way, he got involved with multiple facets, balancing his life between Federal grants from NIH/NSF and the Department of Defense and working with companies, helping to develop new technologies, including surface modification.
Advancing Into Bioprinting
Bioprinting started after Williams moved from Jefferson Medical College where he was taking cells and fat and determining ways of using these regenerative cells in clinical applications, to the University of Arizona. There, he was introduced to a process known as “additive manufacturing.”
Additive manufacturing is a way of creating devices using layer-by-layer construction. At the University of Arizona biomaterials department, Williams had an appointment in material sciences where a number of people were working on additive manufacturing. “They still had never thought about extruding actual cells to use in this, however,” said Williams.
Then fate stepped in and he got a call from someone in DARPA (the Defense Advanced Research Projects Agency). They wanted to put a team together to build an instrument that would print human tissue in the additive manufacturing picture.
“I told them I was already working on this, so it sounded like a perfect fit. That was my introduction to true bioprinting. I have maintained that interest ever since then.” The first project was to print a lymph node, using a three-dimensional printer.
When he heard that the University of Louisville was working on an artificial heart to really attack cardiovascular disease with a more biological approach, it fit in very well with his work. He joined the university and the first thing he discovered was that they needed a better robotic system to print all these tissues.
“We formed a relationship with a company, Advanced Solutions Inc. run by Michael Golway. He and I, and my longtime collaborator, Jay Huling put a plan together to build what we believe is the ultimate robot to print human-tissue equivalent, including eventually being able to print a bioficial heart, a totally functioning heart from a patient’s own cells.”
They built the robot. It’s computer driven and, according to Williams, it has some of the best software to take medical images such as MRIs, CTs, and ultrasound, put them into the computer and then instruct the printer, which is actually an assembly robot, to begin to print out all types of different organ and tissue structures.
“It is multiple generations beyond the simple 3-D model printer that extrudes plastic that is then solidified into a model of something. This does a very similar thing but with a few major components added to it. One, it can print materials that are living and maintain their viability. Also, if you print the old 3-D way, layer by layer by layer, and you want to come back and print a new layer underneath a layer, or in conjunction with a new layer–it won’t let you do that,” Williams explained. “Our robot actually has the ability to come back and print another layer on top of, or on the bottom of the sensory layer. It is another level of assembly and 3-D printing.
“It will recognize where to put the new layer based on Cartesian coordinates and, say, you build part of a heart, but you haven’t put the valves in yet. You put the part you have back into the chamber that this whole thing is built around and then you can come back in and print the valves into their appropriated spots, or you can print the valves outside of the heart to be printed and then use the robot to bring that over and put it into place.”
Since robotic-assisted surgery is already relatively perfected, as Williams notes, this is not so farfetched. Robots already do coronary bypass surgery. “This is the same concept except instead of surgery, the robot is creating the parts. It’s not just 3D printing, it’s bringing something over, suturing something in, it may use biologic glue to glue things together. So, we are building capabilities into this instrument to enable people to go far beyond classic layer-by-layer structures.”
To create these hybrid models, methods of surface modification had to be developed to get cells to adhere to surfaces that are not organic, and also to keep cells from sticking to surfaces they were not supposed to adhere to. Williams explained that the cell biology world uses very simplistic glues to hold things in place. The No. 1 glue is collagen.
“Maintaining cell viability has been a big part of my career for a long time,” he said. “How to develop instruments that can go into an operating room and allow a surgical team to take that tissue and isolate cells that are viable is key. The instruments need to be able to measure the viability of the cells to ensure that they are viable before they are put back into the patient.
“That is the instrument I helped to create. It is built by Tissue Genesis Corp. It allows you to put fat into the device and it sorts out the viable cells so they are ready to be implanted back into a patient, or in our case, be used for the 3-D printing technology to make new hybrid organs and body parts.”
There is another level to the whole project, though. Although Williams and his colleagues can print layer-by-layer cellular structures, without a vascular supply, once the organ being printed gets beyond half a millimeter in depth, there is a loss of oxygen or nutrients to the center of that material.
Williams and his team are currently developing structures that are “pre-vascularized” so the blood flows at the lowest vascular level to keep these cells alive. They have developed a way to use the 3D printing to print capillaries, the smallest blood vessels, so they are able to make very viable structures, particularly the ventricular walls of the heart, with the vascular supply built into it.
Williams boldly said that he believes they are farther ahead of any other group. “We are at the stage of doing implantation of pre-clinical models and are currently planning human clinical trials of pre-vascularized structures for a patch for the human heart. We are not that far away. This would be used on a part of the heart that had very poor or damaged vascular flow for whatever reason, where a bypass graft or a stent will not solve the problem. You have to get to the level of the smallest blood vessels. Using bioprinting to do this is still several years in the future.
“The cells we are isolating are not embryonic stem cells, these are cells from fat, but they are somewhat live, young cells that do survive on a lower oxygen concentration level. So these cells can actually go into a zero oxygen environment and still stay viable for from four to six hours. We have dropped the oxygen concentration to zero and then brought it back up and the cells have remained very viable. So while some cells like brain cells suffer immediately from lack of oxygen, these cells are very robust which makes them perfect for use in this technology.”
Building a Bioficial Heart
To build the entire heart requires separating all the components first and building each one separately. Williams and his team have separated the heart into five parts: the small blood vessels, the large vessels, the valves, the contractile cells, and the electrical conduction system.
“As far as an organ, the heart is relatively simple,” said Williams. “It only has five parts to it. The brain, for instance, is probably the most complex human system. Just the electrical transmission system is extremely complex. In the heart, the electrical system has a specific pathway, easily mapped out.
“What we have been working on is bioprinting the individual parts of the heart. To do this we needed the bio-assembly robot. We took the past year and a half perfecting this tool to get the overall job done. It is tested and we actually are selling them from our lab in Louisville because we want to get them out to as many laboratories and biological research centers as possible so more can be using them to move this area of bioprinting ahead.”
Williams explained that a “normal” heart runs into all types of different problems. One example is that there is only one major artery that feeds a major part of the heart, the left side of the heart. He said that is called that the “widow maker” because when this vessel fails, the patient is at risk of sudden death.
“My concept was, why not start with a new model and build a heart that has redundancy built in? Maybe we can build valves that will last much longer--and again, while the majority of hearts work quite well for 80-plus years--not a bad track record for anything to last--not all do. Some hearts give out quite young. Some have weak spots. It is an amazing organ, but it is not a perfect organ,” noted Williams.
“Why not give these patients a new heart that has all metabolic defects of their original heart corrected? If a patient has a problem with LDL transport leading to arterial sclerosis at a very early age, we have an ability to correct that medically. The cells that we use to make the new coronary artery system would be resistant to the arterial sclerosis as it is built in.
“With a bioficial heart, we just make it a little better. We put in three major coronary vessels instead of just one, so if one fails, the others take over. Build redundancy into it. Also, we want to make this essentially out of all biological components.”
Current Status
Right now the team is currently focusing on the small blood vessels, the large blood vessels, and putting a significant amount of effort into the muscle cells.
“We are also working on printing of the heart valve system. How do you incorporate an electrically conductive system into the heart? But we are not as far along in that area yet. Many others are working on the conductive and valve area, so we will surely borrow from each other as some find more success. There are some groups forging ahead beautifully with the circulation system and valves. We will borrow from their success to build the perfect valves and then use our robot to put that valve into the heart,” said Williams.
At this time, the bioficial heart is Williams’ major target. But, he is also looking toward creating a bioficial pancreas--a way of making a viable tissue that will recognize glucose-produced insulin that can be re-implanted into patients for both type one and type two diabetes.
“I have also been working with the Jewish Hospital (in Louisville) to find a way to do better limb transplants. Currently, hand- transplant patients have to be put onto anti-rejection drugs. I’m thinking about how to use this 3-D printing technology to actually print out the bones, tendons, muscles, nerves, and vascular system, plus the skin to create a hand or limb that can be attached to the patient where no anti-rejection drugs are needed because the whole assembly is made from their own cells.”
But that is the future. Right now, the bioficial heart is his first goal. That project will be ongoing for quite a few years. And every advancement made will add to the future of other areas where bioprinting will help develop new breakthroughs in medical technology. Dr. Stuart Williams will be there, hands-on in all areas.
